Stilbene derivatives for treatment of skin disorders

ABSTRACT

Compounds of the formula ##STR1## wherein R 1  and R 2  each independently are lower-alkyl; or together are alkylene with 3-5 C-atoms in a straight chain; one of the residues R 3  and R 4  is hydrogen and the other is hydrogen or lower-alkyl; R 6  and R 7  are hydrogen or lower-alkyl; R 5  and R 8  are hydrogen, lower-alkyl, lower-alkoxy or halogen; X signifies --O--, --S--, --SO--, --SO 2  -- or --NR 9  ; R 9  is hydrogen, lower-alkyl or acyl; Y is --S(O) m  R 10  or --NHet and, where X is --NR 9  --, --S--, --SO-- or --SO 2  --, also --N(R 11 ) 2  or --OR 12  ; R 10  is lower-alkyl; R 11  and R 12  are hydrogen, lower-alkyl or acyl; --NHet is a 5-8 membered, saturated or unsaturated, monocyclic heterocycle, attached via a N-atom; n is 2, 3 or 4 and m is 0, 1 or 2, are described. The compounds of formula I are useful as agents for the treatment of disorders such as neoplasms, dermatoses or ageing of the skin.

BRIEF SUMMARY OF THE INVENTION

The invention relates to stilbene derivatives of the formula ##STR2##wherein R¹ and R² each independently is lower-alkyl; or together arealkylene with 3-5 C-atoms in a straight chain; one of the residues R³and R⁴ is hydrogen and the other is hydrogen or lower-alkyl; R⁶ and R⁷are hydrogen or lower-alkyl; R⁵ and R⁸ are hydrogen, lower-alkyl,lower-alkoxy or halogen; X is --O--, --S--, --SO--, --SO₂ -- or --NR⁹ ;R⁹ is hydrogen, lower-alkyl or acyl; Y is --S(O)_(m) R¹⁰ or --NHet and,where X is --NR⁹ --, --S--, --SO-- or --SO₂ --, also --N(R¹¹)₂ or --OR¹²; R¹⁰ is lower-alkyl; R¹¹ and R¹² are hydrogen, lower-alkyl or acyl;--NHet is a 5-8 membered, saturated or unsaturated, monocyclicheterocycle attached via a N-atom; n is 2, 3 or 4 and m is 0, 1 or 2 .The compounds of formula I, are useful as agents in the treatment andprophylaxis of neoplasms, dermatoses and ageing of the skin.

DETAILED DESCRIPTION OF THE INVENTION

The invention relates to stilbene derivatives of the formula ##STR3##wherein R¹ and R² each independently is lower-alkyl; or together arealkylene with 3-5 C-atoms in a straight chain; one of the residues R³and R⁴ is hydrogen and the other is hydrogen or lower-alkyl; R⁶ and R⁷are hydrogen or lower-alkyl; R⁵ and R⁸ are hydrogen, lower-alkyl,lower-alkoxy or halogen; X is --O--, --S--, --SO--, --SO₂ -- or --NR⁹ ;R⁹ is hydrogen, lower-alkyl or acyl; Y is --S(O)_(m) R¹⁰ or --NHet and,where X is --NR⁹ --, --S--, --SO-- or --SO₂ --, also --N(R¹¹)₂ or --Or¹²; R¹⁰ is lower-alkyl; R¹¹ and R¹² are hydrogen, lower-alkyl or acyl;--NHet is a 5-8 membered, saturated or unsaturated, monocyclicheterocycle attached via a N-atom; n is 2, 3 or 4 and m is 0, 1 or 2.

Furthermore, the invention is concerned with a process for thepreparation of the compounds of formula I, pharmaceutical preparationsbased on the compounds of formula I, the compounds of formula I in thetreament and prophylaxis of neoplasms, dermatoses and ageing of the skinas well as the use of the compounds of formula I in the manufacture ofpharmaceutical preparations for the treatment and prophylaxis of suchdisorders.

The term "lower" relates to groups with 1-6 C-atoms. Alkyl and alkoxygroups can be straight-chain or branched, such as methyl, ethyl, propyl,isopropyl, butyl, sec.-butyl or tert.-butyl and methoxy, ethoxy,propoxy, isopropoxy, butoxy, sec.-butoxy and tert.-butoxy, respectively.Examples of acyloxy groups are alkanoyloxy groups, preferablylower-alkanoyloxy groups such as acetoxy, propionyloxy, butyryloxy,pivaloyloxy and caproyloxy; or aroyloxy groups such as benzoyloxy,p-nitrobenzoyloxy and toluoyloxy; or aralkanoyloxy groups such asphenylacetoxy. Halogen embrances fluorine, chlorine, bromine and iodine.Preferred heterocyclic residues --NHet are those of the formula --NY' inwhich Y' is --CH₂ --, --CH═, --O--, --S--, --SO--, --SO₂ -- or --NR¹³ --and R¹³ is hydrogen, lower-alkyl or acyl and wherein a total of 3-6C-atoms are disposed between N and Y'. Examples of such residues arepiperidino, pyrrolidino, morpholino, piperazino, N-methylpiperazino,thiomorpholino, thiomorpholino 4-oxide, thiomorpholino 4,4-dioxide aswell as imidazolino and pyrrolo. When R¹ and R² is an alkyl residue with3-5 C-atoms in a straight chain, said residue can be lower alkylsubstituted. Examples of such alkylene residues are 1,3-propylene,1,4-butylene and 1,5-pentylene and lower-alkyl-substituted derivativesthereof such as the residues --C(CH₃)₂ --CH₂ --C(CH₃)₂ --, --C(CH₃)₂--CH₂ CH₂ --C(CH₃)₂ -- and --CH₂ CH₂ --C(CH₃)₂ --CH₂ CH₂ --.

The compounds of formula I can be present as trans or cis isomers orcis/trans isomer mixtures. In general, the trans compounds of formula Iare preferred.

Preferred groups of compounds of formula I are those in which R¹ and R²together are a residue --C(CH₃)₂ --CH₂ --C(CH₃)₂ -- or --C(CH₃)₂ --CH₂--CH₂ --C(CH₃)₂ --; R⁴, R⁵ and R⁸ are hydrogen; and R³ is methyl.Furthermore, the compounds of formula I in which R¹ and R⁸ arelower-alkyl, especially tert,-butyl, are of particular interest.Further, the compounds of formula I in which X is --O-- and Y is --NHet,such as4-[2-[p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenoxy]ethyl]morpholine,are preferred.

Furthermore, compounds of formula I in which X is --S--, --SO--, --SO₂-- or --NR⁹ and Y is --S(O)_(m) R¹⁰ or --NHet are of particularinterest.

Typical representatives of the compounds in accordance with theinvention are the compounds described in the Examples as well as thecompounds listed hereinafter:

4-[2-[p-[(E)-2-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]anilino]ethyl]morpholine;

4-[2-[[p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenyl]thio]ethyl]morpholine;

1-methyl-4-[2-[p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenoxy]ethyl]piperazine;

cis-2,6-dimethyl-4-[2-[p-[2-(E)-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl]propenyl]phenoxy]ethyl]morpholine;

tetrahydro-4-[2-[p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenoxy]ethyl]-2H-1,4-thiazine;

tetrahydro-4-[2-[p-[(E)-2-(6,7,8,9-tetrahydro-7,7-dimethyl-5H-benzocyclohepten-2-yl)propenyl]anilino]ethyl]-2H-1,4-thiazine;

1-[2-[p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl]propenyl]phenoxy]ethyl]pyrrole;

1-[2-[p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl]propenyl]phenoxy]ethyl]imidazole.

The compounds of formula I can be obtained in accordance with theinvention by

(a) reacting a compound of the formula ##STR4## with a compound of theformula ##STR5## or

(b) reacting a compound of the formula ##STR6## with a compound of theformula ##STR7## or

(c) reacting a compound of the formula ##STR8## with a compound of theformula ##STR9## and, if desired, oxidizing a sulphide group representedby X and/or Y in a thus-obtained compound of formula I to a sulphoxideor sulphone group,

wherein the foregoing formulae II-VII R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, X,Y and n are as described above; Q is aryl; A¹³ is an anion of aninorganic or organic acid; R is a lower alkyl group; Z is hydroxy,mercapto, --NHR⁹ or --SO₂ ⁻⁻ M⁺ ; M⁺ is a cation; and L is a leavinggroup.

The reaction in accordance with process variant (a) can be carried outunder the usual process conditions of a Witting reaction. Thereby, thecomponents are reacted with one another in the presence of anacid-binding agent, e.g. in the presence of a strong base such as e.g.butyllithium, sodium hydride, potassium tert.-butylate or the sodiumsalt of dimethyl sulphoxide, but especially in the presence of anethylene oxide which is optionally substituted by lower alkyl such as1,2-butylene oxide, optionally in a solvent, e.g. in an ether such asdiethyl ether or tetrahydrofuran or in an aromatic hydrocarbon such asbenzene or toluene, in a temperature range lying between roomtemperature and the boiling point of the reaction mixture.

Of the inorganic acid ions A⁻⁻ the chloride and bromide ion or thehydrosulphate ion is preferred and of the organic acid ions the tosyloxyion is preferred. The aryl residue Q is preferably a phenyl residue or asubstittued phenyl residue such a p-tolyl.

The reaction according to process variant (b) can be carried out underthe usual conditions of a Horner reaction. Thereby, the components arecondensed with the aid of a base and preferably in the presence of aninert organic solvent, e.g. with the aid of sodium hydride in benzene,toluene, dimethylformamide, DMSO, tetrahydrofuran, dioxan or1,2-dimethoxyethane, or also with the aid of sodium alcoholate in analkanol, e.g. sodium methylate in methanol, in a temperature range lyingbetween 0° and the boiling point of the reaction mixture.

The alkoxy residues RO are preferably lower alkoxy residues with 1-6carbon atoms such as methoxy or ethoxy.

The reaction according to process variant (c) can be carried out in anorganic solvent such as dimethylformamide, conveniently while heating upto the reflux temperature of the reaction mixture. Examples of leavinggroups L are halogen such as chlorine; mesyloxy and tosyloxy. The cationM⁺ in a compound of formula VI is conveniently an alkali metal cationsuch as Na⁺ or K⁺ ; or NH₄ ⁺.

The oxidation of a sulphide group X or Y to a sulphoxide group and theoxidation of a sulphoxide group X or Y to a sulphonyl group can becarried out with oxidation agents such as peracids, e.g. peracetic acidor m-chloroperbenzoic acid. The oxidation of a sulphide group to thesulphoxide group can also be effected by means of periodates such assodium periodate.

The starting materials of formulae II-VII, insofar as they are not knownor described herein, can be prepared in anology to knwon methods ormethods described herein.

Compounds of formulae II and IV and their preparation are described e.g.in German Offenlegung- schriften 2 414 619 and 2 819 213 and EuropeanPatent Specification 2742.

Compounds of formula III can be prepared starting from p-hydroxy-,p-mercapto-, p-amino-, p-alkylamino- or p-acyalmino-substitutedbenzaldehydes or acetophenones, propiophenones or homologues thereof byreaction with a compound of the formula Y(CR⁶,R⁷)_(n) Cl in the presenceof a base such as NaH or by reacting a p-halo-benzaldehyde with an amineof the formula NHR⁹ --(CR⁶,R⁷)_(n) Y or a mercaptan of the formulaHS--(CR⁶,R⁷)_(n) Y in the presence of a base such as K₂ CO₃.

Compounds of formula V can be prepared starting from p-hydroxy-,p-mercapto- or p-amino-, alkyl- amino- or acylamino-substituted benzoicacid esters by reaction with a compound of the formula Y(CR⁶,R⁷)_(n) Cl,reduction of the ester group with Dibal or LiAlH₄ to the correspondingalcohol, replacement of the hydroxy group by bromine, e.g. by reactionwith PBr₃, and reaction of the bromide with a trialkyl phosphite to givea phosphonate of formula V.

Compounds of formula VI wherein Z is hydroxy can be prepared fromcompounds of formula II and compounds of the formula ##STR10## whereinZ' is a protected hydroxy group, e.g. an acetoxy group ortetrahydropyran-2-yl group or a group --OCO--O--lower alkyl,

by a Wittig reaction and subsequent cleavage of the protecting group.Compounds of formula VI in which Z is a SH group can be prepared fromcompounds of formula II by reaction withS-(4-formylphenyl)-dimethyl-thiocarbamate (see EP 58370 B1) andsubsequent cleavage of the thiocarbamate group by treatment with LiAlH₄.

Compounds of formula VI in which Z is a residue --NHR⁹ can be obtainedby preparing a compound corresponding to formula VI with Z=NO₂ from acompound of formula II and p-nitrobenzaldehyde by a Wittig reaction,whereupon the nitro group is reduced, e.g. with Na₂ S₂ O₄ or nascenthydrogen, to the amino group which is finally alkylated or acylated tothe group --NHR⁹.

Compounds of formula VI in which Z is a residue --SO₂ ⁻⁻ M⁺ can beprepared as described in European Patent Specification 58370.

The biological activity of the compounds in accordance with theinvention can be determined e.g. using the test procedures described inGerman Offenlegungsschrift 3 715 955. In testing the activity againstchemically induced (oral administration of dimethylbenzanthracene)mammary tumours in rats the results compiled hereinafter were obtainedwith the compound of formula I,4-[2-[p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenoxy]ethyl]morpholine;

    ______________________________________                                                    Rats    Increase or Increase or                                   Dosage      with    decrease in the                                                                           decrease in the                               [mg/kg/     tumours average number                                                                            average tumour                                day]        [% of   of tumours per                                                                            volume per rat                                p.o.        controls]                                                                             rat         in mm.sup.3                                   ______________________________________                                                50      100     +91       +550                                               100       50     -73       -77                                                200       10     -96       -99                                         Control                                                                              --       100     +242      +714                                        group                                                                         ______________________________________                                    

The compounds of formula I can be used for the topical and systemictherapy of benign and malignant neoplasms, of premalignant lesions aswell as, further, for the systemic and topical prophylaxis of the saidconditions.

Furthermore, they are suitable for the topical and systemic therapy ofacne, psoriasis and other dermatoses which are accompanied by anintensified or pathologically altered cornification, as well as ofinflammatory and allergic dermatological conditionsl. Further, thecompounds of formula I can also be used for the control of mucousmembrane disorders with inflammatory or degenerative or metaplasticchanges. Furthermore, the compounds of formula I can be used, preferablyin topical preparations, for the treatment and prophylaxis oflight-damaged skin (ageing of the skin).

The compositions can be administered enterally, parenterally ortopically. For enteral administration there are suitable e.g.compositions in the form of tablets, capsules, dragees, syrups,suspensions, solutions and suppositories. Preparations in the form ofinfusion or injection solutions are suitable for parenteraladministration.

The dosages in which the preparations are administered can varyaccording to the mode of use and route of use as well as according tothe requirements of the patients. In general, daily dosages of about0.1-100 mg/kg, preferably 1-50 mg/kg, come into consideration foradults.

The preparations can contain inert or pharmacodynamically activeadditives. Tablets or granulates e.g. can contain a series of bindingagents, filler materials, carrier substances of diluents. Liquidpreparations can be present, for example, in the form of a sterilesolution which is miscible with water. Capsules can contain a fillermaterial or thickening agent in addition to the active substance.Furthermore, there can also be present flavour-improving additives aswell as the substances usually used as preserving, stabilizing,moisture-retaining and emulsifying agents, salts for varying the osmoticpressure, buffers and other additives.

The previously mentioned carrier substances and diluents can consist oforganic or inorganic substances, e.g. of water, gelatine, lactose,starch, magnesium stearate, talc, gum arabic, polyalkylene glycols andthe like. It is a prerequisite that all adjuvants used in themanufacture of the preparations are non-toxic.

For topical use the active substances are conveniently used in the formof salves, tinctures, creams, solutions, lotions, sprays, suspensionsand the like. Salves and creams as well as solutions are preferred.These preparations intended for topical use can be manufactured bymixing compounds of formula I as active ingredients with non-toxic,inert, solid or liquid carriers which are usual in such preparations andwhich are suitable for topical treatment.

For topical use there are suitable compositions which can convenientlycomprise active ingredient in the following ranges by weight percent.For solutions, about 0.1-5%, preferably 0.3-2%. For salves or creamsabout 0.1-5%, preferably about 0.3-2%.

If desired, an antioxidant, e.g. tocopherol, N-methyl-q-tocopheramine aswell as butylated hydroxyanisole or butylated hydroxytoluene, can beadmixed with the preparations.

The following Examples illustrate the invention further. Thetemperatures are given in degrees Celsius.

EXAMPLE 1

332 g of2-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethyl]triphenylphosphoniumbromide are suspended in 1.2 l of tetrahydrofuran. 406 ml ofbutyllithium (1.6 molar in hexane) are added dropwise thereto at 0°while stirring. After stirring at 0° for 1 hour a solution of 120 g of4-(2-morpholinoethoxy)benzaldehyde in 400 ml of tetrahydrofuran is addeddropwise to the dark red solution. After stirring at room temperaturefor 2 hours the reaction mixture is poured into 3 l of a methanol/watermixture (6:4) and extracted with hexane. The organic phase is washedwith water, dried over sodium sulphate and evaporated. The yellowish,crystalline residue is recrystallized from ethyl acetate/hexane andgives 123 g of4-[2-[p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenoxy]ethyl]morpholinein white crystals, melting point 107°-109°.

The 4-(2-morpholinoethoxy)benzaldehyde used as the starting material canbe prepared as follows:

92.8 g of 4-hydroxybenzaldehyde are dissolved in 820 ml ofdimethylformamide. After the addition of 228 g of4-(2-choroethyl)morpholine and 415 g of finely powdered potassiumcarbonate the reaction mixture is heated to 100° overnight under argonand while stirring vigorously. The cooled solution is poured into 3 l ofice-water, extracted with ethyl acetate, washed with water, dried andevaporated. The residual dark oil is distilled in a high vacuum andgives 132 g of 4-(2-morpholinoethoxy)benzaldehyde as a yellowish oil,boiling point 145°-150°/33 Pa.

EXAMPLE 2

In a manner analogous to Example 1, from 26 g of triphenyl[1-(1,1,3,3-tetramethyl-5-indenyl)ethyl]phosphonium bromide and 10 g of4-(2-morpholinoethoxy)benzaldehyde there are obtained, afterrecrystallization from hexane, 13.6 g of4-[2-[p-[(E)-2-(1,1,3,3-tetramethyl-5-indenyl)propenyl]phenoxy]ethyl]morpholinein white crystals, melting point 85°-86°.

EXAMPLE 3

0.75 g of a 50% suspension of sodium hydride in mineral oil is suspendedin 10 ml of dimethylformamide. A solution of 5 g ofp-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenolin 30 ml of dimethylformamide is added dropwise thereto while stirringat 0°. After stirring at 0° for 1 hour a solution of 3.6 g ofN-(2-chloroethyl)pyrrolidine in 30 ml of dimethylformamide is addeddropwise thereto. The reaction mixture is subsequently heated to 70° for2 hours, thereafter cooled, poured into ice-water and extracted withethyl acetate. The organic solution is washed several times with water,dried and evaporated. There is obtained a yellow-brown oil which ispurified by filtration over silica gel (eluting agent ethyl acetate+10%ethanol) and recrystallized from hexane. There are isolated 4.5 g of1-[p-[2-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenoxy]ethyl]pyrrolidinein white crystals, melting point 80°-82°.

EXAMPLE 4

In a manner analogous to Example 3, from 5 g ofp-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenoland 4.7 g of 1-(2-chloroethyl)-piperidine there are obtained 5.2 g of1-[2-[p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenoxy]ethyl]piperidinein white crystals, melting point 91°-93°.

EXAMPLE 5

A mixture of 6 g ofp-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenol,4.8 g of 2-chloroethyl methyl sulphide and 10.5 g finely powderedpotassium carbonate in 100 ml of dimethylformamide is heated to 100° for20 hours. The cooled reaction mixture is diluted with water andextracted several times with ethyl acetate. The crystalline residueobtained after drying and evaporating the organic phase isrecrystallized from hexane and gives 5.5 g of methyl2-[p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenoxy]ethylsulphide in colourless crystals, melting point 94°-96°.

EXAMPLE 6

2.1 g of the compound obtained in Example 5 are dissolved in 50 ml ofchloroform and treated slowly at 0° with a solution of 1.2 g ofm-chloroperbenzoic acid (90%) in 10 ml of chloroform. After stirring at0° for 20 hours the mixture is washed with dilute soda solution andwater, dried and evaporated. The thus-obtained yellow oil is filteredover a small silica gel column (eluting agent hexane/ethyl acetate=1:2)and recrystallized from ethyl acetate. There are obtained 1.7 g ofmethyl2-[p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenoxy]ethylsulphoxide, melting point 134°-136°.

EXAMPLE 7

In analogy to Example 6, from 2.8 g of methyl2-[p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenoxy]ethylsulphide and 3.1 g of m-chloroperbenzoic acid (90%) there are obtained,after filtration of the crude product over a small silica gel column(eluting agent hexane/ethyl acetate=1:1) and recrystallization fromethyl acetate, 1.7 g of methyl2-[p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenoxy]ethylsulphone, melting point 169°-171°.

EXAMPLE 8

In analogy to Example 5, from 8.2 g ofp-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl2-naphthyl)propenyl]thiophenol, 12 g of 1-chloro-2-dimethylamino-ethaneand 6.9 g of potassium carbonate by heating to 60° in dimethylformamidethere are obtained, after recrystallization from hexane, 3.5 g ofN,N-dimethyl-2-[[p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenyl]thio]ethylamine,melting point 57°-59°.

EXAMPLE 9

In analogy to Example 8, from 8.2 g ofp-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]thiophenol,10.6 g of 2-chloroethyl methyl ether and 6.9 g of potassium carbonatethere are obtained, after recrystallization from hexane, 5 g of2-methoxyethylp-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenylsulphide, melting point 48°-50°.

EXAMPLE 10

In analogy to Example 8, from 8.2 g ofp-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]thiophenol,12.4 g of 2-chloroethyl methyl sulphide and 6.9 g of potassium carbonatethere are obtained, after recrystallization from hexane, 3.5 g of2-thiomethoxyethylp-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenylsulphide, melting point 65°-67°.

EXAMPLE 11

3 g of sodiump-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenylsulphinate are suspended in 30 ml of dimethylformamide and treated with1.5 g of 2-chloroethyl methyl ether. After heating to 90° for 20 hoursthe mixture is diluted with water, extracted with ethyl acetate, driedand evaporated. The crude product is filtered over a silica gel column(eluting agent hexane/ethyl acetate=4:1) and gives, afterrecrystallization from hexane/ether, 1.8 g of 2-methoxyethylp-[(E)-2-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl]propenyl]phenylsulphone, melting point 104°-106°.

EXAMPLE 12

In analogy to Example 1, from 38.5 g of[1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethyl]triphenylphosphoniumbromide, 45 ml of butyllithium and 13.7 g ofp-[[2-(dimethylamino)ethyl]methylamino]benzaldehyde there are obtained,after filtration over silica gel (eluting agent ethyl acetate, thenethyl acetate/ethanol=1:1 with the addition of 1% triethylamine) andrecrystallization from hexane, 9.2 g ofN,N,N'-trimethyl-N-[p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenyl]ethylenediamine,melting point 46°-48°.

The p-[[2-(dimethylamino)ethyl]methylamino]benzaldehyde used as thestarting material can be prepared as follows:

A mixture of 10 g of 4-fluorobenzaldehyde, 9.7 g oftrimethylethylenediamine and 13.1 g of potassium carbonate in 20 ml ofdimethylformamide is heated to 150° for 16 hours. After cooling themixture is diluted with water and extracted with ethyl acetate. Theorganic phase is washed several times with water, dried and evaporated.The brownish oil (13.7 g) is dried in a high vacuum and is used withoutfurther purification.

EXAMPLE 13

In analogy to Example 12, from 10.4 g of[1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethyl]triphenylphosphoniumbromide, 12.2 ml of butyllithium and 3.4 g ofp-[[2-(dimethylamino)ethyl]amino]benzaldehyde there are obtained, afterrecrystallization from hexane/ethyl acetate, 2 g ofN,N-dimethyl-N'-[p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenyl]ethylenediamine,melting point 102°-104°.

The p-[[2-(dimethylamino)ethyl]amino]benzaldehyde used as the startingmaterial can be prepared as described in Example 12 as a brownish oilfrom 4-fluorobenzaldehyde and 2-dimethylaminoethylamine.

EXAMPLE 14

2.1 g of[1-(6,7,8,9-tetrahydro-7,7-dimethyl-5H-benzocyclohepten-2-yl)ethyl]triphenylphosphoniumbromide are suspended in 10 ml of toluene and treated at 0° with 0.5 gof potassium tert-butylate. After stirring at room temperature for 2hours a solution of 0.94 g of 4-(2-morpholinoethoxy)benzaldehyde in 5 mlof toluene is added dropwise thereto and the mixture is stirred at roomtemperature for 3 hours. After evaporating the majority of the solventthe residue is poured into a mixture of methanol/water (6:4) andextracted several times with hexane. The organic phase is washed withwater, dried and evaporated. Recrystallization of the residue fromhexane gives 0.4 g of4-[2-[p-[(E)-2-(6,7,8,9-tetrahydro-7,7-dimethyl-5H-benzocyclophepten-2-yl)propenyl]phenoxy]ethyl]morpholine,melting point 78°-79°.

EXAMPLE 15

In analogy to Example 1, from 22 g of2-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethyl]triphenylphosphoniumbromide and 9.5 g of p-[[2-morpholino)ethyl]methylamino]benzaldehydethere are obtained, after recrystallization from hexane, 7 g of4-[2-[N-methyl-p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]anilino]ethyl]morpholine,melting point 86°-88°, in white crystals.

The p-[[2-morpholino)ethyl]methylamino]benzaldehyde used as the startingmaterial can be prepared as described in Example 12 as a brownish oil,which crystallizes in the cold, from 4-fluorobenzaldehyde and4-[2-(N-methylamino)ethyl]morpholine.

EXAMPLE 16

Analogously to Example 1, from2-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethyl]triphenylphosphoniumbromide and 4-[2-(tetrahydro-4'H-1,4-thiazin-4'-yl)ethoxy]benzaldehyde1',1'-dioxide there is obtained, after stirring at room temperature for16 hours, working-up, flash chromatography on silica gel withhexane/ethyl acetate (1:2) and crystallization from ethylacetate/hexane,tetrahydro-4-[2-[p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenoxy]ethyl]-2H-1,4-thiazine1,1-dioxide of melting point 144°-145°.

The 4-[2-(tetrahydro-4'H-1,4-thiazin-4'-yl)ethoxy]benzaldehyde1',1'-dioxide can be prepared as follows:

11.6 g of 4-hydroxybenzaldehyde in 160 ml of dimethylformamide areheated to 100° under argon for 2 hours with 15.6 g of4-(2-chloroethyl)-tetrahydro-2H-1,4-thiazine 1,1-dioxide and 21.6 g ofpowdered potassium carbonate. After cooling the mixture is poured on to150 g of ice, extracted three times with 300 ml of ethyl acetate and theorganic phases are washed twice with 150 ml of water, dried over sodiumsulphate and evaporated in a vacuum. The beige, crystalline residue(22.1 g) is used directly for the above Wittig reaction. A sample waschromatographed on silica gel with ethyl acetate/hexane (4:1) andyielded colourless crystals of melting point 101°-102° from ethylacetate/hexane.

The manufacture of dosage forms containing the compounds of formula Ican be effected in the usual manner, e.g. on the basis of the followingExamples.

EXAMPLE A

Hard gelatine capsules can be manufactured as follows:

    ______________________________________                                        Ingredients           mg/capsule                                              ______________________________________                                        1.     Spray-dried powder containing                                                                    200                                                        75% of compound of formula I                                           2.     Sodium dioctylsulphosuccinate                                                                    0.2                                                 3.     Sodium carboxymethylcellulose                                                                    4.8                                                 4.     Microcrystalline cellulose                                                                       86.0                                                5.     Talc               8.0                                                 6.     Magnesium stearate 1.0                                                        Total              300                                                 ______________________________________                                    

The spray-dried powder, which is based on the active substance, gelatineand microcrystalline cellulose and which has an average particle size ofthe active substance of <1 m (measured by means of autocorrelationspectroscopy), is moistened with an aqueous solution of sodiumcarboxymethylcellulose and sodium dioctylsulphosuccinate and kneaded.The resulting mass is granulated, dried and sieved, and the granulateobtained is mixed with microcrystalline cellulose, talc and magnesiumstearate. The powder is filled into size O capsules.

EXAMPLE B

Tablets can be manufactured as follows:

    ______________________________________                                        Ingredients            mg/tablet                                              ______________________________________                                        1.    Compound of formula I as a finely                                                                  500                                                      milled powder                                                           2.    Lactose powder       100                                                3.    Maize starch white    60                                                4.    Povidone K30          8                                                 5.    Maize starch white   112                                                6.    Talc                  16                                                7.    Magnesium stearate    4                                                       Total                800                                                ______________________________________                                    

The finely milled substance is mixed with lactose and a portion of themaize starch. The mixture is moistened with an aqueous solution ofPovidone K30 (polyvinyl pyrrolidone, average molecular weight about40,000) and kneaded, and the resulting mass is granulated, dried andsieved. The granulate is mixed with the remaining maize starch, talc andmagnesium stearate and pressed to tablets of suitable size.

EXAMPLE C

Soft gelatine capsules can be manufactured as follows:

    ______________________________________                                        Ingredients        mg/capsule                                                 ______________________________________                                        1. Compound of formula I                                                                          50                                                        2. Triglyceride    450                                                        Total              500                                                        ______________________________________                                    

10 g of compound of formula I are dissolved in 90 g of medium-chaintriglyceride with stirring, inert gasification and protection fromlight. This solution is processed as the capsule fill mass to softgelatine capsules containing 50 mg of active substance.

EXAMPLE D

A lotion can be manufactured as follows:

    ______________________________________                                        Ingredients                                                                   ______________________________________                                        1. Compound of formula I, finely milled                                                               3.0 g                                                 2. Carbopol 934         9.6 g                                                 3. Sodium hydroxide     q.s. ad pH 6                                          4. Ethanol, 94%         50.0 g                                                5. Demineralized water  ad 100.0 g                                            ______________________________________                                    

The active substance is incorporated into the ethanol, 94%/water mixtureunder protection from light. Carbopol 934 (a crosslinked polymer ofacrylic acid of average molecular weight of about 3,000,000) is stirredin until gelling is complete and the pH value is adjusted with sodiumhydroxide.

We claim:
 1. A compound of the formula ##STR11## wherein R¹ and R² eachindependently is lower-alkyl; or together are alkylene with 3-5 C-atomsin a straight chain; or together are alkylene with 3-5 C-atoms in astraight chain wherein said alkylene is lower-alkyl substituted; one ofthe residues R³ and R⁴ is hydrogen and the other is hydrogen orlower-alkyl; R⁶ and R⁷ are hydrogen or lower-alkyl; R⁵ and R⁸ arehydrogen, lower-alkyl, lower-alkoxy or halogen; X is --O--, --S--,--SO--, --SO₂ -- or --NR⁹ ; R⁹ is hydrogen, lower-alkyl or acyl; Y ismorpholino attached via the N-atom; and n is 2, 3 or
 4. 2. A compound inaccordance with claim 1, wherein R¹ and R² together are aresidue--(CH₃)₂ C--CH₂ CH₂ --C(CH₃)₂ -- or --(CH₃)₂ C--CH₂ --C(CH₃)₂ --.3. A compound in accordance with claim 2, wherein X is --O--.
 4. Acompound in accordance with claim 2, wherein X is --S--, --SO--, SO₂ --or --NR⁹ --.
 5. A compound in accordance with claim 1, wherein R¹ and R⁸are lower-alkyl.
 6. The compound in accordance with claim 1,4-[2-[p-[(E)-2-(5,6,7,8-Tetrahydro-5,5,8,8-tetra-methyl-2-naphthyl)propenyl]phenoxy]ethyl]morpholine.7. A compound in accordance with claim 1 selected from the groupconsistingof4-[2-[p-[(E)-2-(1,1,3,3-tetramethyl-5-indenyl)propenyl]phenoxy]ethyl]morpholine,1-[p-[2-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenoxy]ethyl]pyrrolidine,1-[2-[p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenoxy]ethyl]piperidine,4-[2-[p-[(E)-2-(6,7,8,9-tetrahydro-7,7-dimethyl-5H-benzocyclohepten-2-yl)propenyl]phenoxy]ethyl]morpholine,and4-[2-[N-methyl-p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]anilino]ethyl]morpholine.8. A compound of the formula ##STR12## wherein R⁴ is hydrogen orlower-alkyl; R⁶ and R⁷ are hydrogen or lower-alkyl; X is --O--, --S--,--SO--, --SO₂ -- or NR⁹ ; R⁹ is hydrogen, lower alkyl or acyl; Y ismorpholino attached via the N-atom; and n is 2, 3 or
 4. 9. A compound ofthe formula ##STR13## wherein R⁴ is hydrogen or lower-alkyl; R⁶ and R⁷are hydrogen or lower-alkyl; X is --O--, --S--, --SO--, --SO₂ -- or NR⁹; R⁹ is hydrogen, lower alkyl or acyl; Y is morpholino attached via theN-atom; and n is 2, 3 or
 4. 10. A pharmaceutical composition comprisingan effective amount of a compound the formula ##STR14## wherein R¹ andR² each independently is lower-alkyl; or together are alkylene with 3-5C-atoms in a straight chain; or together are alkylene with 3-5 C-atomsin a straight chain wherein said alkylene is lower-alkyl substituted;one of the residues R³ and R⁴ is hydrogen and the other is hydrogen orlower-alkyl; R⁶ and R⁷ are hydrogen or lower-alkyl; R⁵ and R⁸ arehydrogen, lower-alkyl, lower-alkoxy or halogen; X is --O--, --S--,--SO--, --SO₂ -- or --NR⁹ ; R⁹ is hydrogen, lower-alkyl or acyl; Y ismorpholino attached via the N-atom; and n is 2, 3 or 4 and apharmaceutically inert carrier material.